Multi-drug resistant bacterial infections present an enormous ongoing challenge and infections now occur that are resistant to all current antibacterial options. The pipeline of novel therapeutics to treat drug-resistant infections, especially those caused by Gram-negative pathogens, is all but dry. To combat these multi-drug resistant pathogens, we present an approach that employs mixed ligand-modified gold nanoparticles (1 nm - 5 nm diameter) as antibiotics. Preliminary results indicate that our unoptimized nanoparticles are more potent than many small-molecule antibiotics against K. pneumoniae and E. coli, have essentially equivalent activity against MDR strains of these bacteria, and are less susceptible to evolution of resistance than small-molecule drugs. Preliminary murine studies have also shown no in vivo toxicity. Herein we propose to establish nanoscale structure-activity relationships (NSAR) of active nanoparticles and the mechanistic basis by which these particles inhibit bacterial growth. This information will be employed to optimize our antibiotic nanoparticles and develop new nanoparticles with broad-spectrum activity against all four classes of the Gram-negative ESKAPE pathogens. The in vivo potential of active nanoparticle antibiotics will be established in a murine model of infection.